Multifactorial Involvement of Multidrug Resistance Protein, DNA Topoisomerase II and Glutathione/Glutathione-S-Transferase in NonP- Glycoprotein-Mediated Multidrug Resistance in Human Bladder Cancer Cells

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Abstract
Multiple mechanisms are important in multidrug resistance in urothelial cancers. We investigated the acquisition of a multidrug resistance phenotype in human bladder cancer cells exposed to doxorubicin. Human bladder cancer cell line 5637 and 2 doxorubicin drug-resistant sublines (5637/DR5.5 and 5637/DR50) were used. Measurements were made of the steady state mRNA levels of the multidrug resistance gene (mdr1), multidrug resistance-associated protein (MRP), glutathione-S-transferase-pi and DNA topoisomerase II (topo II) genes, P-glycoprotein (PgP) and MRP expression, glutathione (GSH) and GSH enzyme activity, and topo II catalytic activity. The pharmacokinetics were compared between the parent and the drug-resistant sublines. 5637/DR5.5 and 5637/DR50 cells were 7.6- and 16.2-fold more resistant to doxorubicin and 16.7- and 48.3-fold more resistant to etoposide, respectively, compared with 5637 cells. A dose escalation of doxorubicin increased the MRP expression, GSH levels and glutathione-S-transferase (GST) activity, although no PgP expression was observed in any cell line. Resistance was brought about by decreased drug accumulation through drug efflux, although intracellular daunorubicin concentrations were similar between DR5.5 and DR50 cells. Topo II catalytic activity was undetectable in DR50 cells, but maintained in both the parent and DR5.5 cells. Reduced drug accumulation in doxorubicin-resistant cells was mediated by MRP instead of PgP indicating that MRP-mediated drug efflux functions in a limited manner for drug resistance. An increase in drug efflux via MRP, reduced topo II activity, and increased GSH levels/GSH-related enzyme activities may play major roles in nonPgP-mediated multidrug resistance in urothelial cancers treated with anthracyclines.

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